A combination of technical advances (cell fusion, high resolution G-banding, and molecular cloning) has contributed to an accelerated advance in genetic analysis in mammals. Comparison of linkage relationships of homologous loci provides an opportunity to examine the status of genome organization in animal models of cancer and human inborn errors. We have prepared a biochemical genetic map of the domestic cat, including over 45 loci over the past few years. Included in this map are several classes of loci which participate in human diseases and cancers: (1) endogenous cellular DNA sequences homologous to retroviral RNA genomes, (2) cellular proto-oncogene homologues, (3) growth factor receptors, (4) restriction genes which delimit viral replication; (5) cell surface antigens including the major histocompatibility complex, (6) integration sites of retroviruses, and (7) structural genes for lysosomal enzymes involved in human inborn errors for which there are feline models. Comparative analysis of the feline and human gene maps revealed a striking conservation of linkage association to the extent that approximately 25% of the human genome can be aligned band for band to the corresponding chromomere in the feline genome. The natural history of the endogenous retroviruses and the oncogene homologues during the mammalian radiations has been intepreted in the context of genomic evolution which, in several ways, has recapitulated the chronic processes of neoplastic transformation in man. Eight lysosomal enzymes have been chromosomally assigned in the cat and molecular clones of their human counterparts are being developed in anticipation of gene delivery to feline disease models. The genetic status of related species of the Felidae has revealed a rather recent, morphological divergence and the composite results on one nondomestic species have dramatically demonstrated the importance of abundant polymorphism at the major histocompatibility complex in mammals as a defense against adventitious, virological epidemics in natural populations.